A Comprehensive Review of the Structure Elucidation of Tannins from Terminalia Linn.

Objectives Tannins with complex structures are important plant resources, which are abundant in the genus Terminalia. Various Terminalia species have been playing an important role in traditional medicine system. A systematic scoping review of Terminalia Linn. research literature for tannins was conducted to summarize the structures of tannins and analysis fragmentation pathway characteristics, which could provide references for the structural analysis of tannins from Terminalia Linn. Methods After an update of the literature search up to September 2018, the terms of Terminalia in all publications were analyzed. Electronic searches were conducted in scifinder and PubMed, and the information from 197 articles in all with regard to the tannin structure study was extracted. Results The compounds of 82 tannins from the genus Terminalia were reviewed. According to the structural differences, they can be divided into three categories, hydrolysable tannins, condensed tannins, and complex tannins, respectively. The fragmentation pathways of 46 identified tannins were analyzed, and the fragmentation rules of tannins were speculated according to different types. Conclusion This review has attracted attention to the active substances in this species such as the tannins summarized in further study. How to improve the extraction and purification technology of tannins from genus Terminalia is an urgent problem to be solved.


Introduction
Plants of the genus Terminalia (family Combretaceae) are widely used in traditional medicine all over the world [1].
ere are about 250 Terminalia species, of which at least 50 are used as food [2]. Many species have biological activities including antitumor, anti-inflammatory, wound healing, antifungal, antibacterial, and antiviral activities [3][4][5][6][7]. In particular, Terminalia chebula, an Indian species, is well noted as the king of plants in Ayurveda for its extensive medicinal use [8].
e plants mainly include tannins, polyphenols, triterpenoids, flavonoids, aliphatic compounds, and other active ingredients, among which tannins and polyphenols are the main constituents [9].
Tannins are a kind of polyphenolic compounds with complex structures in plants. ey are classified into three groups on the basis of their structures: hydrolysable tannins, condensed tannins, and complex tannins. Usually, their molecular weights are greater than 500 Da. Tannins are widely distributed in various plants, and they are considered defensive molecules to protect plant tissues from herbivorous attacks because of their astringent taste [10]. It has been reported that several natural tannins and related compounds have various biological activities, including antioxidant, antitumor, hypolipidemic, hypoglycemic, and antibacterial activities [11][12][13][14]. Takashi Tananka isolated terflavin A and B, tercatain, and tergallagin from the leaves of Terminalia catappa Linn. in 1986 [15]. Since then, more than 82 tannins have been isolated from the fruits, barks, leaves, and galls in the plants of the genus Terminalia. e mass spectrometric data of these tannins and the structure analysis of the compounds are discussed.
is review aims to provide references for the structure identification of tannin constituents in the plants of Terminalia Linn. In the further study of phytochemistry, the research field of medicinal activity of this important genus should be highlighted and guided.

Data Sources and Searches.
Electronic searches were conducted in scifinder and PubMed for articles up to September 2018, using terms related to tannins, Terminalia, and MS. Searches were conducted with no date or language restrictions.

Eligibility and Selection.
e titles and abstracts of 197 articles were screened, respectively, and the full text of the article was reviewed to obtain sufficient information. Any disagreements regarding the inclusion of articles were resolved through discussion and consensus.

Data Extraction.
e final data extraction included the following five categories: (1) general characteristics (compound name, source, structure, and journal name); (2) MS data (compound name, ion Source, ion mode, fragments, and journal name); and (3) MS fragmentation pattern (fragmentation rules and journal name).

Results and Discussions
3.1. Tannins. Tannins are widely distributed in plants. ey can be classified into three types according to their structural differences. Hydrolysable tannins are a group of compounds formed by phenolic acids and their derivatives through glycoside bonds or ester bonds with glucose or polyols. ey are further divided into gallotannins containing only galloyl groups, ellagitannins containing hexahydroxydiphenoyl group(s), and hydrolysable tannin oligomers divided into dimers, trimers, and tetramers according to the number of glucose nuclei [16]. Condensed tannins are a class of compounds formed by the carbon-carbon bond polymerization of flavane-3-ol such as catechins or their derivative gallocatechin. Complex tannins are a class of compounds composed of flavane-3-ol, the unit of condensed tannins, and hydrolyzed tannins, which are partially linked by carbon-carbon bonds.
On the basis of the structural differences, they are divided into different types. Compounds 1-74 are hydrolysable tannins. Among them, compounds 1-11 (

MS Data of Tannins.
e MS data of the tannins from the genus Terminalia (family Combretaceae) are shown in Table 6 as summarized. According to the compiled MS data, this review provides a useful and fast way for the identification of tannins.
QM fragmentation cleaves the single bond between subunits in B-type procyanidins to form a single quinone resulting in two possible product ions.

Biological Activity
Natural compounds are important sources of drugs. More and more attention has been paid to the scientific investigation of natural bioactive compounds which may yield new compounds or leading compounds that can overcome the limitations of currently used drugs. At present, some achievements have been made in the study of tannins, but there are still some deficiencies. Tannins extracted from plants are often a collection of monomers of different kinds of tannins mentioned above. eir bioactivities are closely related to the action of these tannin monomers which need further studies. e reported biological activity of these tannins from the genus Terminalia (Family Combretaceae) was summarized briefly.

Antioxidant
Activity. Ellagitannins such as compounds 18, 48, and 70 were found to be the major components in Terminalia bellirica, which exhibited the antioxidant and hepatoprotective activities [167]. Compounds 11, 20, 30, 33, and 43 exhibited great antioxidant activity in both chemicalbased and cellular-based antioxidant assays, and compound 11 showed the highest cellular antioxidant activity [168]. Compound 11 has the highest potency for DPPH-, NO-, and ONOO-scavenging activity with IC50 ranging from 5 to 20 μM, 0.20, and 0.06 μM, respectively [169]. Compounds 33 and 43 showed the highest increase in GSH, and compound 30 produced the highest increase in SOD among four tannins [170]. Compounds 28 and 62 had in vitro antioxidant activity and in vivo antioxidative stress effects [171]. A lot of research showed that antioxidant compounds are related to a variety of oxidative stress-related diseases, such as cardiovascular diseases, neurodegenerative diseases, and cancer [172].

Antimicrobial and Antivirus
Activity. Compound 18 could inhibit biofilm formation, quorum sensing, and toxin secretion. is indicated that corilagin might be an effective antibacterial compound [183]. Compound 11 efficiently blocked entry of HCV of all major genotypes and also of the related flavivirus Zika virus [184]. Compound 11 could effectively inhibit the replication of RABV by the miR-455-5p/SOCS3/STAT3/IL-6-dependent pathway [185]. Compounds 28, 44, and 62 reduced the HCV replication [186] via a dual mechanism through preventing the formation of cccDNA and promoting cccDNA decay [187].

Antidiabetic Activity.
It was confirmed that compound 18 can regulate diabetes, by exhibiting antidiabetic, antihyperlipidemic, and antioxidant properties in STZ-induced diabetic rats [188]. Compound 11 could maintain normal   [190]. Compound 48 was confirmed to inhibit TGF-beta 1-induced antifibrotic activity in choroid-retinal endothelial cells (RF/6A) [191] and inhibit TNF alpha induced proangiogenic and proinflammatory activities in retinal capillary endothelial cells [192]. e study of nanoparticles plays an important role in tannin activity and application. Bioavailability and bioactivity of a component are often altered once it is embedded into nanoparticles. Zheng Li fabricated the PPE with 16.6% (w/w) of punicalagin A, 32.5% (w/w) of punicalagin B, and a small amount of ellagic acid-hexoside and ellagic acid (1%, w/w). PPE-gelatin nanoparticle suspension had similar effects in inducing late stage of apoptosis and necrosis compared to PPE [193]. Guo-Bin Song fabricated a natural promising protein protective film through soluble dietary fiber (SDF)-tannin nanocluster self-assembly which characterized to possess a broad spectrum of antimicrobial properties and are beneficial to food preservation [194]. e field of nanoparticles plays an important role in the utilization of tannin activity with great development potential.
ere is a lack of research on the interaction between proteins and tannins from Terminalia Linn., but the tannin extracted from persimmon fruits has been reported to have a high affinity to pancreatic lipase and possessed pancreatic lipase inhibition with IC50 of 0.44 mg/mL. Molecular docking showed that this interaction is mainly caused by the hydrogen bonding and π-π stacking [195]. It has been demonstrated that the very simple tannin methyl gallate was able to stack with itself or with caffeine [10]. 18 Evidence-Based Complementary and Alternative Medicine association of tannins should also take into account the interaction between tannins and proteins, as it governs their bioavailability. e interactions between tannin-tannin and tannin-protein are still unclear. Changes in protein bioactivity and structure induced by tannin binding need further studies. Current limited metabolic studies showed that tannins are mainly metabolized as urolithins in the gut [196]. Urolithins are characterized to possess antitumor, antioxidative, and antiinflammatory activities in vitro, which can be isolated and purified by high-speed counter-current chromatography. Urolithin A, a major punicalagin metabolite, could result in autophagy in SW620 colorectal cancer (CRC) cells at submicromolar concentrations [197]. It is very helpful for drug design to clarify the biotransformation of tannins in vivo.
erefore, it is necessary to accelerate the development of the technical means for the analysis of bioactive compounds of natural medicines, so as to realize the large-scale development and utilization of tannin monomer compounds. e physiological activity of tannins has been fully confirmed, but the physiological mechanism of its various pharmacological effects is still not clear, limiting the development and utilization of tannins.

Conclusion
Terminalia species have been widely used in various traditional medical systems such as Siddha, Traditional Chinese Medicine (TCM), and Western, Southern, and Central African medicinal systems [8]. Apart from reports on the ethnopharmacological uses of many Terminalia species, few studies have carried out rigorous studies on the medical properties, mechanisms, and phytochemistry of this important genus. is may be due to the fact that tannins are the main active constituents in many Terminalia species. Tannins have strong polarity, high molecular weight, complex structure, active chemical properties, and are extremely difficult to crystallize which make them difficult to extract, separate, purify, and identify, and the quality standard is not easy to control. erefore, they are so complex that they are not suitable for drug design and often overlooked as potential for drug discovery. us, how to improve the extraction and purification technology of tannins from genus Terminalia is an urgent problem to be solved. Researchers need to further determine the structure-activity relationship between tannins and their functions, clarify the mechanism of action, and carry out safety toxicological evaluation to ensure safety and stability, so as to make tannins hopeful to become new drugs on the market. e structures of 82 tannins from the genus Terminalia were reviewed in this paper. e fragmentation pathways of identified tannins were analyzed, and the fragmentation rules of tannins were speculated, which could provide references for the structural analysis of natural medicines and their analogues. In further research, researchers may need to pay more attention to the species and the active substances such as the tannin summarized above.

Conflicts of Interest
No competing financial interest exists.

Authors' Contributions
Zihao Chang and Qiunan Zhang contributed equally to this work.